This application is for renewed funding for years 14-18 of 2R01 AI33144. Our broad objective is to determine the genetic mechanisms influencing the immune response to live viral vaccines and to answer the question of how and to what degree heterogeneity in immune responses depends upon polymorphisms of immune response genes. Measles kills over 500,000 children annually. Because of the primary role of measles virus receptors (SLAM and CD46) in virus entry, Toll-like receptors (TLRs) in stimulating both innate and adaptive immune responses, and cytokines as intercellular protein messengers in the immune response cascade, gene polymorphisms of these receptors and cytokines will be the focus of this application. Having previously examined the role of HLA genes, we now focus on the influence of these additional gene polymorphisms on measures of humoral and cell-mediated immunity (CMI) to a live viral vaccine 'measles' as a probe and model to further explore the influence of immunogenetics on vaccine response variability. To accomplish these goals, we propose to test the following hypotheses: 1) Significant associations exist between polymorphisms of measles virus receptor genes (SLAM and CD46) and variations in humoral and CMI responses to measles vaccine, 2) Significant associations exist between polymorphisms of a prioritized set of Toll-like receptor genes (TLR 2,3,4,5,6,7,8, and 9) and their associated intracellular signaling molecules, and humoral and CMI responses to measles vaccine, 3-4) Significant associations exist between polymorphisms of a prioritized set of cytokine genes (IFN1, 2, 3, IL-12, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12A, IL-12B, TNF1 and GM-CSF) and selected corresponding cytokine receptor genes (IL-1R1, IL-1R2, IL-1RN, IL-2RA, IL-2RB, IL- 2RG, IL-4RA, IL-5RA, IL-6R, IL-6ST, IL-10RA, IL-10RB, IL-12RB1, IL-12RB2, IFNAR1, IFNAR2, IFNGR1, IFNGR2, TNFRSF1A, TNFRSF1B, CSF2RA and CSF2RB), and humoral and CMI responses to measles vaccine and 5) Significant associations exist between selected prototypic Th1 (IL-2, IL-12(p40), IFN3), Th2 (IL- 4, IL-10), and innate/inflammatory (IFN1) secreted cytokine protein levels and humoral and CMI responses to measles vaccine. This application is innovative in examining the effect of immune response gene polymorphisms on the heterogeneity of measles vaccine immune responses in a population. These studies will also provide specific knowledge for understanding measles immunity, as well as provide a model framework for estimating the contribution of immune response gene polymorphisms on the heterogeneity of immune responses to a viral vaccine. Lastly our work may provide knowledge important to the development of new viral vaccines, particularly against measles, by understanding genetic restrictions that prevent protective immune responses to vaccine. In turn, it may be possible in the near future to engineer viral vaccine candidates that can overcome such restrictions. PUBLIC HEALTH RELEVANCE: This application studies genes that influence and determine the human immune response to measles vaccine. This knowledge will allow a better understanding of how measles immunity develops after vaccination and why a range of immune responses occurs. Globally, measles kills over 500,000 children annually, and small outbreaks continue to occur in the U.S.